The objective of the research is to characterize, and examine the basis for, the atrophic changes in articular cartilage which result from immobilization of a joint. A particular aim is to determine how the reversibility of these degenerative changes is affected by subsequent exercise and whether vigorous usage of a recently immobilized joint may lead to osteoarthritis (OA). Our results to date indicate that, in comparison to cartilage from the contralateral knees, cartilage from the knees which had been casted for 6 weeks showed an increase in water content and decreases in thickness, Safranin-O staining, uronic acid (UA) content,and net proteoglycan (PG) synthesis. In addition, the ability of both newly-synthesized and total tissue PGs to interact with hyaluronic acid (HA) to from aggregates was diminished, due to a defect in the HA-binding region of the core proteins. If the casts were removed and the animals were then allowed to ambulate ad libertum for 3 weeks all of these changes were reversed. However, knee cartilage from 3 dogs which had been run daily on a treadmill for 3 weeks after removal of casts exhibited continuing decreases in thickness and UA content, even though net PG synthesis was increased in comparison to that in cartilage from the contralateral (non-immobilized) knee. The abnormality in both 35S and total tissue PGs which precluded their interaction with HA persisted. Three additional dogs were exercised on a treadmill for 6 months after removal of casts which had been applied for 6 weeks. In these studies, the defects caused by casting all disappeared and OA did not develop. The cartilage, however, remained thinner than the control despite a continuing increase in PG synthesis and UA content. The proposed studies will examine, specifically (1) the mechanisms by which PG metabolism and aggregation are affected by immobilization and (2) the possibility that exercise of the limb after lengthier intervals of casting may lead to OA.